Stop the Metformin Madness

I have never been a fan of Metformin. It seemed too good to be true. Many years ago I had a conversation with a researcher about all of its possible therapeutic indications. His lab was actively pursuing the anti-cancer angle. That should have been a clue that Metformin might be causing more damage than we recognized, but it wasn’t. At that point, I was still enamored with the wonders of pharmacology and hadn’t yet begun my path toward understanding medication adverse reactions. Indeed, it wasn’t until very recently, when a family member began suffering from one of these reactions, that I began my investigation in full. This is what I learned.

With the increasing rates of obesity and associated metabolic disturbances, drugs that purportedly reduce those indicators are primed for growth. Like the push to expand statin prescription rates from 1 in 4 Americans to perhaps 1 in 3, millions have been spent increasing the therapeutic indications and reach for this medication. Amid all the excitement over this drug, one has to wonder if it isn’t too good to be true. In our exuberance to get something for nothing, to have cake, if you will, have we overlooked the very real risks and side effects associated with Metformin? I think we have.

Metformin and Vitamin B12 Deficiency

As we’ve reported previously, Metformin leaches vitamin B12 and to a lesser degree B9 (folate) from the body. One study found almost 30% of Metformin users are vitamin B12 deficient. For the US alone, that’s almost 15 million people who could be vitamin B12 deficient and likely do not know that they are deficient. What happens when one is vitamin B12 deficient?

Metformin, Pregnancy and Maternal and Fetal Complications

Considering that half the population is female, many of whom are on Metformin and may become pregnant, we must consider the potential effects of Metformin-induced vitamin B12 deficiency during pregnancy. As troubling as the effects are of B12 deficiency are on non-pregnant individuals, during pregnancy they can be devastating. Vitamin B12 deficiency during pregnancy leads to an increased incidence of neural tube defects and anencephaly (the neural tube fails to close during gestation). Once thought to be solely related to folate deficiency (vitamin B9) which Metformin also induces, researchers are now finding that B12 has a role in neural tube defects as well.

Scan the internet for Metformin and infertility and you’ll see long lists of fertility centers boasting the benefits of this drug. During pregnancy, the exuberance for vitamin M is palpable, although entirely misplaced. Early reports suggested Metformin would reduce an array of pregnancy complications including gestational diabetes. The data supporting these practices were mixed at best. At worst, however, they were downright incorrect. Metformin, it appears, may evoke the very conditions it was promoted to prevent during pregnancy and then some. Additionally, recent research suggests Metformin alters fetal development and induces long term metabolic changes in the offspring, likely predisposing the children to Type 2 Diabetes, an epigenetic effect perhaps.

Metformin Inhibits Exercise-Induced Insulin Sensitivity

As if those side effects were not enough to question mass Metformin prescribing practices, it appears that Metformin reduces any gains in insulin sensitivity that normally would be achieved from exercise. I cannot help but wonder if Metformin impairs insulin signaling in general. The cancer research suggests that it might.

Metformin and Mitochondrial Damage

Recall from high school biology, the mitochondria are those bean shaped organelles inside cells that are responsible for cellular respiration or energy production. Through a variety of pathways, the mitochondria provide fuel for cell survival. In addition to cellular energy production, mitochondria control cell apoptosis (death), calcium, copper and iron homeostasis and steroidogenesis. In essence, mitochondria perform the key tasks associated with cell survival, and indeed, human survival. Damage the mitochondria and the cellular dysfunction or death will occur. Damage sufficient numbers of mitochondrion and chronic, multi-symptom illness arises.

As we have come to learn, many pharmaceuticals, environmental toxicants and even dietary deficiencies can impair mitochondrial functioning and induce disease processes that are often difficult to diagnose and treat. Metformin is no different. Metformin impairs mitochondrial functioning quite significantly by several mechanisms and, in doing so, sets off a cascading sequence of ill-effects.

At the center of metformin’s mitochondrial damage is its affect on the most basic of mitochondrial functions – ATP (cellular energy) production. Metformin reduces mitochondrial ATP production in skeletal muscle by as much as 48%. Sit with that one for a moment, a 48% reduction in cell fuel. Imagine functioning at only half capacity. This would make basic activities difficult at best and exercising to lose weight a very unlikely proposition. Imagine similar reductions in ATP production were observed in the brain or the heart or the GI tract (which, when on Metformin are likely), the types of disturbances we might see become quite clear: neurocognitive decline, psychiatric instability, neuropathy, heart rate, rhythm and blood pressure abnormalities, along with gastrointestinal distress to name but a few. Underlying all of these symptoms, and indeed, all mitochondrial dysfunction, is an overwhelming sense of fatigue and malaise.

Metformin Alters Immune Reactivity via the Mitochondria

Some researchers argue that the mitochondria are the danger sensors for host organisms; having evolved over two billion years to identify and communicate signs of danger to the cells within which they reside. The signaling is simple and yet highly refined, involving a series of switches that control cellular energy, and thus, cellular life or death. When danger is present, energy resources are conserved and the immune system fighters are unleashed. When danger is resolved, normal functioning can resume.

If the danger is not resolved and the immune battles must rage on, the mitochondria begin the complicated process of reallocating resources until the battle is won or the decision is made to institute what can only be described as suicide – cell death. Cell death is a normal occurrence in the cell cycle of life. Cells are born and die for all manner of reasons. But when cell death occurs from mitochondrial injury, it is messy, and evokes even broader immune responses, setting a cascade in motion that is difficult to arrest.

Metformin alters this process, first by damaging the mitochondrial ATP factory and reducing energy production capacity and then by inhibiting the signaling cascades that would normally respond to the danger signals. The double hit fundamentally alters immune function and I would suspect predisposes those who take Metformin to more infections and an array of inflammation based disease processes. More details on this in a subsequent post.

Metformin and the Statins: Beware

The mechanisms through which Metformin derails mitochondrial functioning are complex but likely related to depletion of coQ10, an enzyme involved in what is called the electron transport chain within the mitochondria. CoQ10, also referred to as ubiquinole and ubiquinone, is critical for mitochondrial functioning. Recall from a previous post, statins, like Lipitor, Crestor and others also deplete coQ10 and from a pharmacological perspective these mechanisms are implicated in the development of atherosclerosis and heart failure.

“statins may be causative in coronary artery calcification and can function as mitochondrial toxins that impair muscle function in the heart and blood vessels through the depletion of coenzyme Q10 and ‘heme A’, and thereby ATP generation.”

CoQ10 depletion is also implicated in the more common statin-induced side effects like muscle pain and weakness and in severe cases, rhabdomyolysis. Since Metformin and statins are regularly co-prescribed, the potential for severely depleted mitochondria and significant side effects is very high. Consider muscle pain and weakness among the first signs of problems.

My Two Cents

When we contrast the reduction in glucose mediated by Metformin with the damage this medication does to the mitochondria and immune signaling, along with its ability to leach vitamin B12, block insulin sensitivity and reduce aerobic capacity, one cannot help but wonder if we are causing more harm than good. Admittedly, obesity and hyperglycemia are growing problems in Western cultures. As we are coming to learn, however, obesity itself is not linked to the diseases processes for which many drugs like the statins and Metformin are promoted to protect against – obesity paradox. Growing evidence suggests that obesity is indicative of mitochondrial dysfunction and chemical exposures which then may provoke impaired insulin sensitivity and hyperglycemia and continued fat storage versus metabolism. If this is true, simply reducing circulating glucose concentrations, in an effort to reduce obesity and the purported health problems associated obesity, will do nothing to treat the underlying problem.

Insulin resistance and the associated hyperglycemia are environmental and lifestyle mediated problems that should be reversible with environmental and lifestyle changes. Having said that, those lifestyle and dietary changes will fail unless we consider the underlying mitochondrial damage initiated by dietary choices, pharmaceutical and other environmental exposures. For that we must dig deeper into mitochondrial functioning and correct what we can.

I believe obesity and hyperglycemia are symptoms of damaged and dysfunctional mitochondria, partly mediated by lifestyle, partly iatrogenic (pharmaceutically induced) and likely epigenetic. If we are to solve the ‘obesity’ problem and prevent the damage mediated by hyperglycemia, we have to address these variables. Failing to do so serves no one except those who profit from our continued ill-health.

Chandler Marrs MS, MA, PhD spent the last dozen years in women’s health research with a focus on steroid neuroendocrinology and mental health. She has published and presented several articles on her findings. As a graduate student, she founded and directed the UNLV Maternal Health Lab, mentoring dozens of students while directing clinical and Internet-based research. Post graduate, she continued at UNLV as an adjunct faculty member, teaching advanced undergraduate psychopharmacology and health psychology (stress endocrinology). Dr. Marrs received her BA in philosophy from the University of Redlands; MS in Clinical Psychology from California Lutheran University; and, MA and PhD in Experimental Psychology/ Neuroendocrinology from the University of Nevada, Las Vegas.

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29 Comments

I know this thread is a couple of years old but I’m curious about something. I’ve been using Metformin (2.5 grams per day) for 14 years (I’m 37) with no noticeable negative health consequences. In fact, I can run a marathon in 2 hours 45 minutes. I wondered what effect Metformin might be having on my athletic performance which is how I stumbled on this. It hardly seems like it’s reducing my aerobic capacity. I also found this site which mentions a study that concluded an increase in anaerobic capacity and performance: http://suppversity.blogspot.co.nz/2015/10/first-study-to-demonstrate-ergogenic.html
Is there in merit in that study or would I better served by just going off the metformin? I’m pretty sure i could get away with it as these days I have a low carb diet.

After researching Berberine (berberis aristata), I have replaced Metformin with 1,500 mgs a day or 500 mg per meal each day. I told my doctor what I was going to do, even though my B12 status tested very high, I do not like to take drugs because I believe what nature provides can help me. I am also on a ketogenic diet that keeps high and medium glycemic foods off my plate. I have given up starches and sugars in all forms, and eat no grains, corn, peas, beans, rice, pasta, wheat, barley, oats or artificial stuff. My doctor has asked me to come back in 2 months for an A1C blood test to see what I have been able to accomplish with Berberine. I do take a multitude of supplements, especially vitamins C, D, and a B complex as well as a multi vitamin and some specialties as well such as extra minerals like chromium, zinc, selenium, magnesium, potassium and not so much calcium because I get that in abundance in my diet. I have had the fatigue syndrome before, and getting off of one of my blood pressure meds helped fix that (calcium channel blockers). I decided 34 years ago to take control of my own health with diet and exercise rather than leaving my fate up to the medical organizations. I do lots of research and have learned that, as a diabetic, there is much I can do to control my own life and blood glucose readings.

My story is similar to yours and I wondered how you test results turned out. I have been on metformin for two weeks but follow keto strictly now and exercise daily. I’m just curious about how you’ve progressed. Thanks

I feel very fortunate in coming across your site and this post as I am deathly ill after only one dose of Metformin, I can’t recall feeling so ill without full blown morning sickness or a horrific flu shot induced nausea as for me I am always debilitated by the prevention less than ever I have been a flu. This of course could be luck on my side however, I’m never so lucky taking such shots. If I take Pneumonia shots I get it so I’ve stopped taking any of these. Your post fills me with so many questions as I’ve been diagnosed with Lupus (2008) after a heart attack and open heart surgery in 2005 at the ripe old age of 36. I have no good cholesterol but even still the bad isn’t nearly in the high range. My health has steadily gotten worse but I was worse off after following the med regimines. I went from 105 to 168 in weight it was horrible. I quit the Meds and the lipids and life began to get better. The last 3 years though I’ve went through and am basically over Menopause. I’ll be 48 in October but my womanhood left me in 2012 and she’s not returned since other than my periods but now they have been gone sine 2014. They have given me a natural hormone supplement cream to begin and just diagnosed me with diabetes this week.

I took the metformin yesterday and as stated am deathly ill, I don’t want to take this if anything I want more than anything to omit medication in my life as to me it seems the more they give the shorter our life spans are probably becoming especially as women. I am always in need of b12 and vitamin D and no my diet isn’t perfect as if anything I’ve become fearful of food bc of my sugar going haywire as well as mixing that in with the hot flashes of Menopause and you end up ready to take a vacation at the nuthouse.

I love this article and thank you for it but may I ask for those of us who aren’t really up to speed on what we can do on our own vitamin and supplement wise if you would be so kind as to share with us some regiments we should be using in general just to be healthy as well as if you see yourself falling to ruin as so many of us seem to be with so many commonalities here what we can begin to take to restore our bodies and maybe avoid these medications all together. It may seem shocking for me to be so naive as to what to do but run of the mill folks don’t get the time with doctors we would like and when we finally do the last thing on their mind is vitamins and supplements because who would pay their office rent or pay off their vacation homes if we could get our good health from nature? It’s a sad but very real way of the medical profession and drug industries but what’s worse is we are the lab rats of the medical profession.

I’m sure I’m not alone in wanting more than anything to find healing in that which god gave us to heal with or at least have the chance to try to be self aware and self sufficient in healing what so many doctors are destroying within us. After reading this it makes me wonder if I’m suppose to have sugar problems, be done with Menopause and no longer hopeful of ever feeling better than I do now but only to suffer a quickening of my final days arrival if I’m not already within them. It is so disheartening when you wake up knowing you’re just 47 and you don’t know if you will ever have a full life ahead of you anymore.

Would you share with us a way to come back to life and good health if it’s just to get us started in what we can begin as a regiment that’s not something Larry king is selling on an infomercial (unless it works as therein lies the problem when you can’t trust doctors to care and not be pharmaceutical bonus hounds and the only other source we have is infomercials because we don’t have access to naturalist or holistic doctors who try nature to nurture first). It’s scary for us and very intimidating and it’s not because we are uneducated or lacking in sense it’s fear of the unknown and unease of the products we have access to. I am a college educated woman with my degree and then some …but I’m missing the most important other some, please share if you can how you came to normalize your b12 levels, what we can start out with that will boost these in us from nature and restore at least that part of us. It seems it should be so easily done but I guess I’m just weary and worn down from all no one cared to help us do as well as oftentimes angry because I feel so stupid for not knowing where to begin to bring my body back to some happiness again.

Thank you very much and know your post is so appreciated and I am so hoping to see more about this from you. Thank you for sharing and caring enough to give those of us the resources we aren’t always able to get or know where to or how to begin to ask for.

I am going to ask a “could it be” question. I will seek advise of my physicians before any changes but need to know. Since my heart surgery in 2013, I have experienced extreme muscle fatigue and wasting. This seemed to be epsidoic but we were removing and adding back meds a lot trying to find a cause(none found yet) I have had tons of very extreme testing done and during the corse of all this found COQ10 to be a huge help. Just recently I was feeling great for about 3 months. This month I went back on Metformin, within 2 weeks I couldn’t even walk without total exhaustion.
I am back off it now and feeling better but we will attempt to reintroduce it in the future to find out if its the culprit.
Could Metformin deplete energy or something in some peoples mitochrondial and not others?

My mom had a similar experience with metformin. She had been on it and other meds for years, declining health. We eventually got her clean and she did great for 3-4 years and then went back on metformin (against my wishes). Within a few weeks, she was confused, weak and couldn’t stand. Her experience is what prompted me to dig into the research and write this. I have another article on metformin mechanisms, you might consider reading it before re-introducing it. Metformin does all sorts of things that are contraindicated with diabetes. Dietary changes would be better. Also consider reading my article on thiamine and diabetes (almost all diabetics are thiamine deficient). Thiamine tends to control blood sugar quite well, among other potential benefits b/c of its role in mitochondrial energy production. Good luck.

I had a HbA1c of 16.5 and next test got it to 5.4. My doc said it was a great result for metformin but it was my work to find solutions again and he does not know but I am off it. I did have issues with lipids but fatty liver and work through it myself, not taking his statins, not taking valporate not telling him as he will not understand.
So it is LCHF, but with greens, I am unsure about dairy as I am bullish about fermented foods and make kefir, viili, kombucha and sauerkraut. It is coming together. I dropped 20kg and excercise is key to maintaining my focus and mood, and intermittent fasting. I would advocate that for autophagy benefit. So as well visualise your goal. I like the focus on mitochondrial function, tie it in to gut health and be kind, it is a process.

If metformin interferes with the development of insulin sensitivity, how do people such as your mother and many others manage to wean off it with diet and exercise? Ipsofacto, their insulin sensitivity had to increase to allow their blood glucose levels to normalise to the point where they could go off metformin. I am very curious about this, as I would like to wean off metformin. Going off it abruptly was a disaster, so I’d like to be able to increase my insulin sensitivity before trying to wean again. I have PCOS and horrible insulin resistance, which is fully controlled by metformin and diet.

She worked with a physician who specialized in functional medicine. He put her on a whole host of supplements. It took a while and is still not fully stabilized (plus, she doesn’t always follow her diet strictly). Also, we weened her off but reducing the dosing gradually, over many months so that her body could re-equilibrate. With any medication, especially if one has been on it for a long time, there has to be a very slow and gradual reduction so that the body’s own systems can come back online. How long it takes, depends a lot on the drug, the length of time one has been on the drug and the individual’s unique body chemistry and lifestyle considerations.

Weaning was a smart idea. I went off cold turkey and became very ill. What type of diet does your mother do? I am very curious about the exercise aspect – does being on met truly prevent any improvement in insulin resistant? Seems like exercise would be a useless tool for weaning then. I wanted to try Berberine, but have read bad things about that too. It’s so frustrating!

She swims daily and that seems to help. Exercise is important for a number of reasons and it helps with insulin sensitivity, even as you are weaning. She is supposed to be on a gluten free, mostly starch free diet. She was tested for food allergies/sensitivities and we learned that she had several. She doesn’t follow it as well as she should and when she doesn’t she often gets sick w/ digestive issues. Organic foods are important as many of the chemicals in the commercial foods damage gut bacteria where nutrients are absorbed. I don’t know anything about berberine, so I cannot help there. What I can say, is do your homework, be smart about how you approach this and take control. It’s possible to be healthy, it just takes some work.

My husband and I both take metformin. I am more worried about him. He has CMT disease,(high arches and muscle weakness) which from what I understand strips the mylin sheath from his nerve endings; but since starting Metformin his feet seem to be numb all the time. It is doing veery little to nothing to regulate his sugars and he is really being “a good boy” when it comes to eating properly. Since reading this article I am wondering if perhaps he could regulate the sugar on his own without the Metformin, or should we possibly get a different drug for him.?

See a physician who specializes in functional medicine. He or she can help you to come off of the medication safely and fix your diet or other nutritional deficiencies so that you no longer need metformin.

Ive been on metformin which is generic for glucaphage. Was in biabetic coma in 1997.
Im still on metformin twice a day,along with glimipride
I have blood test every 3 months, and no signs of any problemd

Hi. I have been type 2 diabetic for 10+ years. My doctor suggested I start taking Metformin a couple of years ago. I did for one week. I had diarrhea so bad that I was weak. I went back to my doctor, gave her back the pills and told her she could keep them! We, as adults, have the choice to refuse any medication that the doctor offers. After all, it’s our body. Right? Don’t allow your doctor to bully you into taking certain medication! Make an informed decision about what medication you put into your body. Do your own research, don’t depend on some pamphlet available through the company that manufactures the medication. Of course they are not going to tell you the negative things about their product. Find a resource that is honest about the medication, the good and the bad.

This article is very disturbing. I’ve been on metformin for a few years now… first I was on HBP meds and about 6 mos after that my BS kept running about 125-150ish so Dr put me on metformin. Many years before these diagnoses I was diagnosed with fibromyalgia, as a couple of the other commenters mentioned. I am eating Keto to try to get off of all meds but it’s soo difficult to be 100%. This article makes me want to strive even harder to be 100%. It is very disappointing to hear about working out… I am half tempted to go off the metformim after reading this. My Dr knows my concerns about taking meds and assures me I’m taking a low dose but this article doesn’t say anything about any dose being more or less dangerous and how long it takes for damage to be done.

It is disturbing. It’s not clear from the research how long it takes for the damage to be done or undone once the medication is stopped. I did the research and wrote this article because my mother was on this medication and began having problems. She had been on it for years, along with a bunch of other medications and began having all sorts of problems all at once. I guess she had reached her limits. We gradually got her off of each of the meds over the course of a year or so and cleaned up her diet. She was great for a few years, healthy, exercising regularly, and then her blood sugar began creeping up again. Rather than change her diet, which had fallen back into old habits, her doctor put her back on metformin. Within a few months she had deteriorated so badly that she couldn’t walk, was confused and was generally becoming very ill, very quickly. We stopped the metformin, found her another doctor who has taken a more holistic and functional approach, cleaned up her diet again, put her on a bunch of supplements and helped to rehabilitate her. It took several months for her recover, but she is once again, doing quite well. She swims regularly and is back to where she was prior to the metformin. I would suggest finding a physician who specializes in functional medicine. They seem to have the appropriate knowledge and perspective to tackle these types of issues, more so than the more traditionally trained physicians.

This article is the most biased article on Metformin I have come across so far. Do not believe this article except that it leaches Vit. B12. We have to take sublingual Vit. B12 tablets everyday to cover up the deficiency this metformin causes.

Metformin is a real wonder drug even though the author of this article do not believe it. This is because there have been numerous studies done on it since 2 decades and it has amazing benefits. Most of the diabetics are taking it and have benefited from it taking if for years.

I have been taking it myself and even my weight reduced considerably when I started the Metformin after being diagnosed diabetic.

Low carb diet may get your sugar control in normal range but if you find your sugar levels are going little above normal or yr HbA1c is more than 5.8, pl continue taking Metformin. Maximum dosage you can take is 2.5 g in a day. Take sustained release form and always take it after meals

This is a concerning article. I am a type II and due to weight gain my endo has suggested I go from taking only insulin but combine it with metformin slow release. The normal stuff made me quite ill. Its a vicious circle. Insulin, weight gain, control and this with lots of exercise. Very,very difficult to control it all

I have Neuropathy in my legs and feet. I have been taking Metformin for years. I need to use a cane to walk because of balance. You did not talk about the Neuropathy part of it in this newsletter. What can I do. I am just getting worse each year. Thanks. Can I just stop taking Metformin? The doctor says I am pre diabetic.

I deal with many people in pre-diabetic state and also with diabetes mellitus already. The best thing you can do is do everything in your power to reverse diabetes. I do have a question though: it is striking me odd that you have neuropathy and taking Metformin for years in pre-diabetic state.

Neuropathy can also occur from being “floxed” which means having taken antibiotics in the quinolone family of drugs of which the most commonly prescribed ones are:

Normally, neuropathy develops after several years of full blown diabetes 2 and not in pre-diabetic state. It is also not typical for pre-diabetes the use of Metformin. If you are in true pre-diabetic state, it is commonly reversible by stopping all sugars and sugar substitutes (anything that is sweetened by anything) and reducing/stopping high insulin spiking grains (wheat, corn (as dry used as popcorn or flour, the fresh corn is OK), barley, rye, rice and several more that are less inflammatory) and reduce those fruits that have high sugar content (persimmons, pomegranate, watermelon, etc.,), stop all juices and smoothies, shakes, alcohol, and increase fresh produce and low sugar/high fiber fruits like berries, and organic meats and water.

Most people with neuropathy benefit from magnesium supplements, so read some of the articles on what “floxed” people do to help themselves; you find many articles on that subject at hormonesmatter.com

Hi Alice,
The metformin neuropathy can be caused by a multitude of factors, all of which inevitably begin with damaged mitochondria, which is induced by, believe it or not, vitamin and mineral deficiencies. Vitamins/minerals act as co-factors in a number of processes that influence cell function and when they are deficient, those functions slow or cease altogether and dysfunction and illness ensue. Metformin in particular, depletes coq10, B12, but also thiamine. We have several articles on neuropathy that you might consider, simply search neuropathy on the site that they will appear. Here is one that might help. http://www.hormonesmatter.com/diabetes-thiamine-treatment-opportunity/

I’ve known about Metformin as a treatment for insulin resistance and PCOS for some time. I had no idea of its potential for ill effect. It seems just another example of a drug that masks or makes worse underlying health problems.

This article is of interest to me…one who has been on metformin for several years (I’d have to check how many). I am now on glimeperide and also 10 units of Levemir a day. I have been diagnosed with Fibromyalgia, IBS, and have almost no energy at all. These are only 2 of the problems besides diabetes that I have. My question: Is it possible to go off of metformin with the help of my endocrinologist? Thank you and I sure would like to see the next article, hope to see it in my inbox. Sincerely ,
L Mercer (age 65).

I am not a physician, so I am afraid I cannot give medical advice. Physicians who specialize in functional medicine can help you safely adjust or come off your medications and treat the root causes of your illnesses rather than simply treat the symptoms. You might look here for a physician in your area https://www.functionalmedicine.org/
I should note, your symptoms are not uncommon to mitochondrial dysfunction.